Professor Jodie Simpson

A breath of fresh air

Professor Jodie Simpson's pioneering research has changed the focus of asthma treatment and promises new relief for many who suffer from the disease.

Making the transition from pure science to medical research involved a leap of faith for Professor Jodie Simpson, but the accomplished asthma researcher has not looked back since joining the University of Newcastle's leading respiratory group. The chemistry graduate's science background prompted her to approach research questions with a different perspective and subsequently led to a breakthrough finding about asthma subtypes that has brought her international recognition in the field.

Simpson was appointed as a research assistant with the respiratory team, based at the Hunter Medical Research Institute (HMRI), in 1997 after completing her Honours in chemistry. When she began studying asthma, the accepted treatment paradigm was using steroid-based medications to target inflammation in the airways caused by increased levels of eosinophils (a type of white blood cell). However, Simpson was puzzled by the fact that some asthma sufferers had normal levels of eosinophils, which led her to question whether there could be more than one type of the disease.

"I could never understand why it was assumed that all asthma was due to increased eosinophils when only about half of the patient studies we saw had that characterisation," Jodie reflects.

Encouraged by a small number of scholarly reports advocating a similar theory, Jodie embarked in 2002 on an ambitious PhD project investigating the inflammatory pathways of asthma, counting cells in sputum samples and analysing levels of enzymes and proteins. Simpson concluded that there were four subtypes of asthma and, significantly, identified a non-eosinophilic category common among people who did not respond well to conventional, steroid-based treatments. This subtype is characterised by higher levels of a different white blood cell, called the neutrophil.

Jodie's research led to a randomised control trial, conducted in Newcastle, which produced another breakthrough finding, published in 2008 in the American Journal of Critical and Respiratory Care Medicine. The study established that treating people who suffered from non-eosinophilic asthma with macrolide antibiotics successfully reduced their neutrophil levels and resulted in a clinical improvement in their condition. "It was a small study, but novel at the time, and it showed that identifying the inflammatory phenotype was important for the effective management of asthma," Simpson explains.

That original eight-week, 45-person study has since evolved into a four-year, 420-person national trial led by Professor Peter Gibson, with whom Simpson has worked closely, and funded by the National Health and Medical Research Council. The $2.9 million AMAZES trial (Asthma and Macrolides: the Azithromycin Efficacy and Safety Study) seeks to determine whether treating asthmatics with macrolides in addition to their normal medication can reduce the incidence of severe attacks, known as exacerbations, and ease their general symptoms.

"The focus of the AMAZES study is treatment but it has all developed from the original idea of characterising subtypes of asthma," Jodie says. "Instead of a blanket treatment for everyone who has asthma, we can now move towards a more individualised approach, drawing from a range of effective treatments."

As well as working on the AMAZES trial, Simpson has instigated a series of peripheral studies aimed at increasing understanding of non-eosinophilic asthma. One project is testing the extent to which sufferers can reduce their steroid medication without a detrimental impact on their health; another is testing alternatives to macrolide antibiotics for reducing inflammation; and a third is investigating possible triggers for the condition, such as reflux and cough. She is also working with colleague Dr Katie Baines to advance the characterisation of asthma subtypes through gene expression.

"Substantial progress has been made in understanding non-eosinophilic asthma but there is far more that we need to know," Jodie acknowledges. "We want to attack it from all angles."

Off to a flying start

How does a chemistry graduate come to supervise a medical trial for her first postdoctoral project? For Dr Jodie Simpson, the encouragement of her supervisor and mentor Professor Peter Gibson was critical to her rapid and successful induction to the field of asthma research.Professor Gibson is co-director of the HMRI Viruses, Infections/Immunity, Vaccines and Asthma (VIVA) Program and has been an influential figure in Simpson's career.

"What he did from the beginning was provide opportunity," Jodie says. "I came to the team with an Honours degree in chemistry and he gave me the chance to learn about the clinical side of research and participate in it. To be able to lead a clinical trial for my first project after my PhD was such a wonderful opportunity."

The insight into clinical issues that Jodie gained from working with Professor Gibson has greatly enhanced her work. "When you are in the lab counting cells and measuring proteins, you can lose the sight of the fact that this is all about a person out there who is struggling to breathe and function," she advises. "Working in this team, where we can combine basic science and clinical work, has given me a more rounded perspective."

The mother of young children acknowledges that the supportive environment at the University and HMRI for researchers with young families has been critical to her work. "As researchers we are passionate about what we do and it is important to have the support to remain productive during periods where we might have to modify our working commitments."

Career Summary

Biography

Jodie Simpson is a senior research fellow in The University of Newcastle’s Priority Research Centre for Asthma and Respiratory Disease and the current holder of the Australian Respiratory Council’s Ann Woolcock Research Fellowship.

Her research focuses on the inflammatory biomarkers of airways disease and she has a particular interest in innate immune pathways and their role in airways disease. She has developed several important assays for the assessment of inflammatory mediators in airway secretions and continues to work on assessment of novel markers of airway inflammation.

In 2005, Jodie completed her PhD where she identified and characterised four inflammatory phenotypes in asthma based on the presence of absence of increased sputum eosinophil and neutrophil proportions. This work has led to further investigations of asthma inflammatory phenotypes using gene expression profiling and recently the identification of novel biomarkers for asthma and COPD.

Dr Simpson designed and conducted the first RCT of macrolide antibiotics in severe refractory asthma, this research was pivotal in her success with a large NHMRC project grant awarded in 2008 to investigate macrolide antibiotic therapy in asthma as a multi-centre RCT (The AMAZES study).

In her earlier work, Dr Simpson demonstrated that macrolide antibiotics are an effective anti-inflammatory therapy in non-eosinophilic refractory asthma. She is currently working on the AMAZES study collaborating with centres around Australia and working on 2 sub-studies, the first looking at macrophage phagocytosis and the second investigating airway and systemic inflammation in asthma subtypes.

Jodie has actively presented her work at national and international scientific meetings and has authored over 50 papers in peer reviewed journals. She is an active participant in research service and teaching as representative on TSANZ research subcommittee and the supervisor of 4 research higher degree students.

Research ExpertiseJodie Simpson is a senior research fellow in The University of Newcastle’s Priority Research Centre for Asthma and Respiratory Disease and the current holder of the Australian Respiratory Council’s Ann Woolcock Research Fellowship. Her research focuses on the inflammatory biomarkers of airways disease and she has a particular interest in innate immune pathways and their role in airways disease

Qualifications

PhD (Medicine), University of Newcastle

Bachelor of Science, University of Newcastle

Bachelor of Science (Honours), University of Newcastle

Keywords

COPD

asthma

asthma and COPD

clinical trials

immune response

induced sputum

inflammation

inflammatory mediators

Fields of Research

Code

Description

Percentage

110203

Respiratory Diseases

100

Professional Experience

UON Appointment

Title

Organisation / Department

Professor

University of NewcastleSchool of Medicine and Public HealthAustralia

Professor

University of NewcastleSchool of Biomedical Sciences and PharmacyAustralia

Background: Asthma is a heterogeneous inflammatory disease and eosinophilic, noneosinophilic and neutrophilic forms are recognised. While clinically similar to eosinophilic asthma... [more]

Background: Asthma is a heterogeneous inflammatory disease and eosinophilic, noneosinophilic and neutrophilic forms are recognised. While clinically similar to eosinophilic asthma, patients with non-eosinophilic asthma have different responses to treatment and little is known about the triggers of symptoms and inflammation. Objective: This study sought to characterise asthma control, exacerbation frequency and potential triggers of non-eosinophilic and specifically neutrophilic asthma such as infection, gastroesophageal reflux disease, and rhinosinusitis. Methods: Adults with asthma (n=65; doctor's diagnosis plus demonstrated response to bronchodilator and/or airways hyperresponsiveness to hypertonic saline) were recruited from the Respiratory and Sleep Medicine Ambulatory Care Service at John Hunter Hospital, NSW, Australia. Questionnaires were administered to assess gastroesophageal reflux disease, rhinosinusitis and asthma control. A sputum induction was performed and sputum was processed for assessment of inflammatory cells, infection, and lipid laden macrophages (Oil Red O). Results: Participants with neutrophilic asthma (n=11, 23%) had a higher frequency of primary care doctor visits for asthma exacerbations and a high prevalence ( > 70%) of chest infections in the previous 12 months. There was also an increased prevalence of rhinosinusitis (64%) and increased symptoms of gastroesophageal reflux disease compared to those with eosinophilic asthma. Conclusions: The clinical pattern of neutrophilic asthma is different from paucigranulocytic and eosinophilic asthma with evidence of abnormal upper airways responses. Specific and targeted treatment of these airway problems may assist in the control and management of neutrophilic asthma.

Airway inflammation is allergic aspergillosis (ABPA) is typically characterised by increased eosinophils. We have recently reported increased sputum neutrophils in ABPA that correlates with the extent of bronchiectasis on HRCT. In this study we sought to evaluate the role of the neutrophil chemoattractant IL-8 in ABPA. 29 adults with ABPA (20 with central bronchiectasis, ABPA-CB; 9 with serological ABPA, ABPA-S) were compared with 21 normal controls, and 9 asthmatics without Af sensitisation. Induced sputum was examined for cellular differential, IL-8 protein by ELISA and immunocytocheraistry, and IL-8 gene expression by semi-quantitative RTPCR. Sputum supernatant IL-8 was 66ng/mL in ABPA-CB, 65 in ABPA-S, 3.5ng/mL in controls and 3.6ng/mL in asthma (p < 0.001 ). Sputum IL-8 correlated with sputum neutrophils (r=0.63) and FEV| % predicted (r=-0.7). IL-8 containing cells were predominantly neutrophils. IL-8mRNA levels were 108 and 24ag/mL in the ABPA groups, compared to 1.2 and 2.4ag/mL in asthma and controls (p < 0.05). Conclusion: In ABPA there is elevated IL-8 gene expression and protein release, that correlates with the degree of airflow obstruction and neutrophil influx. IL-8 may be an important cytokine mediating inflammation and lung damage in ABPA.

Airway inflammation is now regarded as a key feature of asthma. Since the relationship between clinical asthma severity and airway inflammation in children with asthma is not know... [more]

Airway inflammation is now regarded as a key feature of asthma. Since the relationship between clinical asthma severity and airway inflammation in children with asthma is not known, we sought to examine this issue in this study. Children with asthma (n=146) and healthy controls (n=37) were recruited from respiratory clinics and primary care practitioners. Clinical asthma severity was assessed by questionnaire, followed by spirometry, airway responsiveness to hypertonic (4.5%) saline, and sputum induction. Selected sputum was processed with DTT, and assayed for cell differential, and ECP. Adequate sputum samples were obtained from 78% of children. Sputum eosinophils were elevated in children with persistent asthma (n=35,3.8%), and frequent episodic (FE) asthma (n=39,2.3%), compared to infrequent episodic (IE) asthma (n=72,1.5%), and controls (n=37,1%). Sputum eosinophils were higher in persistent asthma than IE asthma (p < 0.05). Similar changes were present with ECP: persistent 375ng/mL, FE 220ng/mE, IE 113ng/mL, control 139ng/mL (p < 0.05). Conclusion: Sputum eosinophils and ECP are related to clinical asthma severity in childhood asthma.

ABPA is an important complication of chronic asthma resulting from hypersensitivity to the fungus Aspergillus Fumigatus ( AF}. ABPA is characterised by an intense immune response ... [more]

ABPA is an important complication of chronic asthma resulting from hypersensitivity to the fungus Aspergillus Fumigatus ( AF}. ABPA is characterised by an intense immune response with increased use of oral steroids and potentially progressive lung disease. The aim of this study was to determine if treatment of subjects with ABPA with the antifungal agent Itraconazole (Itz) reduced airway and systemic inflammation. Methods: A randomised double blind placebo controlled trial was performed in stable subjects with ABPA (n=29). Subjects with cystic fibrosis ere excluded. The diagnosis of ABPA was based upon; the presence of asthma, IgE sensitisation to Af. a total serum IgE of lOOOIl'/mL or greater and serum IgG to Af or central bronchiectasis on CT scan. Subjects received Itz 400mg per day (n=15) or placebo (n=14) for 16 weeks. All subjects were reviewed monthly with history, spirometry. sputum induction to measure airway inflammation, serum total IgE and IgG to Af and blood eosinophils. Results: Subjects receiving Itz had a greater reduction in sputum eosinophils from baseline (median fall of 94.5%) compared to placebo (45.4%. p < 0.01 ). Those on Itz had a fall in sputum total cell count from baseline (43.9%) compared to a rise in those on placebo (rise 10%. p=0.049). Subjects that received Itz also had a reduction in systemic immune activation; there was a fall in serum IgE (3IOIU/mL) compared to placebo (rise ISIU-'mL, p < 0.01) and a fall in IgG to Af(15.4IU/mL) compared to placebo (rise 3.7IU - mL, p=0.03). Conclusion: Treatment of subjects with stable ABPA with Itz 400mg daily reduces eosinophilic airway inflammation along with measures of systemic immune activation. These results imply that Itz is a potential adjunctive treatment for ABPA and this should be further investigated with larger studies of lone term clinical efficacv.

Rationale: Epidemics of acute asthma associated with thunderstorms occur intermittently worldwide, though airway inflammation during these acute episodes has not been characterise... [more]

Rationale: Epidemics of acute asthma associated with thunderstorms occur intermittently worldwide, though airway inflammation during these acute episodes has not been characterised. The aim of this study was to characterise airway inflammation in acute thunderstorm asthma. Methods: Cases were recruited after presentation to the emergency room (ER) \vith acute asthma immediately following a thunderstorm (n=6). They were compared to controls that were atopic asthmatics that had presented with acute asthma to the ER prior to the thunderstorm. Subjects had spirometry, sputum induction and allergy skin tests acutely and at review 4 weeks later. Results: Thunderstorm (TS) cases were more likely to have a history of hay fever and less likely to be on inhaled steroids prior to presentation. Both groups had a similar degree of moderate to severe acute airways obstruction (p=l ,0). TS cases had elevated sputum eosinophils (14.8% of total cell count) compared to controls (1%, p < 0.01). TS cases had higher sputum eosinophil cationic protein (ECP) (11686ng/mL) compared to controls (1883, p=0.02) acutely. When adjusted for IS use, TS cases had a risk ratio for elevated sputum eosinophils of 2.3 (1.1-4.5). Conclusion: Airway inflammation in acute thunderstorm asthma is characterised by more sputum eosinophilia and eosinophil degranulation compared to other causes of acute asthma.

Although airway inflammation is recognized as a key feature of asthma, the characteristics of airway inflammation in children with acute severe asthma are not well defined. The ai... [more]

Although airway inflammation is recognized as a key feature of asthma, the characteristics of airway inflammation in children with acute severe asthma are not well defined. The aim of this study was to describe the characteristics of airway inflammation in children with an acute exacerbation of asthma using sputum cell counts and fluid-phase measurements and to examine the changes in these parameters upon resolution of the exacerbation. Children (n = 38) presenting to the Emergency Department with acute asthma underwent successful sputum induction using ultrasonically nebulized normal saline (n = 22), or expectorated sputum spontaneously (n = 16). Sputum induction was repeated at least 2 wk later when the children had recovered (n = 28). Sputum portions were selected, dispersed and total and differential cell counts performed. Neutrophil elastase and EG2-positive eosinophils were assessed and fluid-phase eosinophil cationic protein (ECP), myeloperoxidase (MPO), interleukin-8 (IL-8), and IL-5 were measured. During the acute exacerbation the median (range) total cell count was 8.4 x 10 6 /ml (0.5 to 190.3), and fell significantly at resolution to 1.3 x 10 6 /ml (p < 0.01). The inflammatory cell infiltrate was mixed and included eosinophils (0.8 x 10 6 /ml), neutrophils (3.3 x 10 6 /ml), and mast cells. EG2 + cells were high and correlated with the degree of airflow obstruction (r = -0.5, p = 0.02). They decreased significantly at resolution as did supernatant ECP (1,078 versus 272 ng/ml), suggesting that eosinophils were activated during the exacerbation. MPO was 220 ng/ml at exacerbation and fell significantly to 1 ng/ml at resolution. Levels of IL-8 and IL-5 were elevated during the acute exacerbation and IL-8 concentrations decreased at resolution. In conclusion, airway inflammation can be studied in children with acute asthma by sputum induction. Airway inflammation is present during an acute exacerbation of asthma, and is characterized by infiltration and activation of both eosinophils and neutrophils. The heterogeneity of airway inflammation in acute asthma may influence response to corticosteroid therapy.

In mild asthma there is typically an infiltrate with eosinophils, which improves with corticosteroid therapy. Asthma can persist despite high dose inhaled corticosteroid therapy (... [more]

In mild asthma there is typically an infiltrate with eosinophils, which improves with corticosteroid therapy. Asthma can persist despite high dose inhaled corticosteroid therapy (ICS). Aim: The aim of this study was to establish the characteristics of airway inflammation in asthma, which persists despite high dose inhaled corticosteroids. Method: Adults (n=73) with asthma and persistent symptoms who were taking =1000g ICS underwent hypertonic saline challenge and sputum induction. Sputum was dispersed using dithiothreitol and assayed for total cell count, cellular differential, supernatant eosinophil cationic protein (ECP ng/mL), myeloperoxidase (MPO ng/mL) and interleukin-8 (IL-8 ng/mL). Subjects were categorised into 4 groups based upon the presence or absence of airway hyperresponsiveness (AHR) and increased sputum eosinophils (E; being > 5%). Results: Subjects with eosinophilic AHR (EAR n=16) had 22% E, compared to those with noneosinophilic AHR (NEAR, n=40) who had 1.5% E. Those with asthma in remission (normal AHR and E; n=14) had 1.2% E. Neutrophil % was similar in all 3 groups (p > 0.05). ECP was highest in the EAR positive group (7572) compared with NEAR (2834) and remission (504; p = 0.001). MPO was elevated in NEAR (275) and EAR (253) compared with remission (189; p = 0.05). IL-8 levels were highest in NEAR (86.2) compared to EAR (36.5) and remission (12.9; p = 0.03). Conclusion: Asthma which remains symptomatic despite high dose ICS consists of 2 different inflammatory patterns. While some have typical eosinophil inflammation, the most common pattern is cellular (neutrophil and eosinophil) activation, with suppressed eosinophil counts. This may be mediated by IL-8 secretion. There is heterogeneity of airway inflammation in symptomatic asthma.

Associate Professor Jodie Simpson from the University of Newcastle's
Priority Research Centre for Asthma and Respiratory Diseases will visit
China from 18 November to 5 December 2014 on the Australia-China Young
Scientists Exchange Program.